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Treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past several years with the availability of targeted agents.

As the role of angiogenesis and tumor proliferation in RCC has come to light, agents effective at multiple sites along these pathways have been developed and demonstrated to be efficacious in varying degrees. These agents include:

Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR)

mTor is an intracellular kinase that regulates cell proliferation and angiogenesis. Everolimus (RAD001) is an oral inhibitor of mTOR, which has been shown in a single-arm phase II trial to have antitumor activity in pretreated metastatic RCC (Jac, ASCO, 2007).

This randomized, double-blind, multicenter, phase III study was carried out to compare efficacy of everolimus to placebo in treatment of metastatic RCC having progressed during VEGFr-TKI therapy with either sunitinib or sorafenib.

Materials and Methods

Patients with metastatic RCC who had progressed either during or less than six months after VEGFr-TKI therapy with sunitinib, sorafenib, or both, were randomized in a 2:1 fashion to receive everolimus (10 mg daily) to placebo, both in the setting of best supportive care.

Physicians and patients were blinded to the arm assigned.

Inclusion criteria included: diagnosis of metastatic RCC with a clear cell component; measurable disease; and progressive disease on VEGFr-TKI therapy. Patients were not excluded if they had also received previous treatment with bevacizumab and/ or cytokine-based treatment.

At the time of progressive disease, patients and physicians were unblinded, and patients were permitted to cross over from the placebo arm to the everolimus arm.

Two interim analyses were planned during this study; at the time of the second interim analysis, an Independent Data Monitoring Committee recommended early cessation of the study to allow patients receiving placebo to receive everolimus. This recommendation was accepted, and the second interim analysis now serves as the final analysis.

Results

During the period from September 2006 through October 2007, 272 patients were randomized to receive everolimus, and 138 to placebo.

Previous treatment included sunitinib in 45% of patients, sorafenib in 29%, and both in 25%.

Differences in baseline patient characteristics between the two arms were not significant.

At the time of final analysis, 51% of patients receiving everolimus continued on treatment, versus 22% of those receiving placebo.

Sixty-eight deaths have been observed, and this study will continue to assess the secondary endpoint of overall survival.

The most common treatment toxicities encountered were stomatitis (36% versus 0% with everolimus versus placebo, respectively), anemia (28% versus 15%), and aesthesia (28% versus 20%). A 3% incidence of grade 3-4 pneumonitis was encountered in the group receiving everolimus, as were a 3% incidence of hypercholesterolemia, and a 12% incidence of hyperglycemia. Ten percent of patients receiving everolimus experienced treatment discontinuation due to toxicity versus 4% of patients receiving placebo.

No significant difference in health-related quality of life was seen between the two groups.

Author's Conclusions

The authors conclude that everolimus is associated with a 70% relative risk reduction in progressive disease/ death from metastatic RCC.

They note that this benefit is seen across all subgroups, with a favorable safety profile and no significant detriment to quality of life.

They go on to conclude that everolimus should be the standard of care for metastatic RCC progressing through VEGFr-TKI therapy.

Although these treatments are described as second-line in this study, many patients had received several prior treatments and were in fact embarking on third- or fourth-line therapy.

The benefit of everolimus over placebo is clear from this study, and the authors’ conclusion that everolimus should be a standard of care in this setting seems valid, particularly given the fact that no other agent has been demonstrated to be as efficacious to date.

Having said this, with the recent advent of targeted agents available to treat metastatic RCC, the timing and sequence with which they will be ultimately used to achieve the best outcomes is as of yet undetermined.

Everolimus appears to be quite efficacious in this study; direct comparisons to VEGFr-TKI therapies in the form of further trials would be very interesting.

Additionally, use of these agents in combination with one another or with conventional chemotherapy could demonstrate even further benefit.

For current patients, however, everolimus represents a treatment option that is effective and seems tolerable, with little impact on quality of life. Certainly, this is a major addition to the current armory used to treat RCC, and should indeed be used to provide benefit to patients in this setting.

Jun 6, 2012 - Continuing use of bevacizumab (Avastin) in combination with second-line chemotherapy improves overall survival and progression-free survival in patients with metastatic colorectal cancer who have progressed after discontinuation of first-line bevacizumab and chemotherapy, according to the results of a phase III study presented at the annual meeting of the American Society of Clinical Oncology, held from June 1 to 5 in Chicago.